The initiation of the herpes simplex virus lytic replication cycle depends upon the coordinated expression of the viral (IE) immediate early genes. These genes are controlled by a complex multiprotein enhancer assembly that consists of viral and cellular components. Studies of the various components, protein interactions, viral and cellular functions provides both a model for cellular transcriptional regulation as well as insights into the mechanisms utilized by the virus. The focus of the laboratory is the identification and characterization of the critical components of this regulatory pathway. The mammalian coactivator HCF-1 is one of the more complex factors involved in both the assembly of the enhancer complex and the activation of the IE genes. Studies focus upon both functions during the viral lytic cycle as well as in normal cellular processes. The importance of both is underscored by the complex viral-cell interactions that impact the lytic and latent states of the viral life cycle. These studies (i) have delineated functional domains of the protein; (ii) developed molecular models for HCF-1 domains; (iii) identified cellular and viral proteins that interact with various domains; (iii) elucidated a role for HCF-1 in the regulation of HSV DNA replication; (iv) characterized a unique mechanism for the regulation of protein-protein interactions via site-specific proteolytic processing; (v) demonstrated the biochemical mechanism involved in HCF-1 transcriptional coactivation; and (iv) identified HCF-1 as the essential component of both HSV and VZV viral IE gene expression.